The immune system has long been thought of only as a means for removal of antigen, often by induction of inflammation. However, immune cells are known to contain and release opioid peptides. We have demonstrated the presence of opioid precursor message as well as the opioid peptides themselves in immune cells in blood, lymph nodes and inflamed tissue. Furthermore, we were able to show that activated lymphocytes that migrate specifically to sites of inflammation, contain opioid peptides. However, resting lymphocytes in general do not contain significant amounts of opioid peptides. The inflammatory cells release opioid peptides when cell surface receptors are activated by local factors (i.e. corticotropin-releasing factor (CRF) and interleukin-1 (IL-1)), which are upregulated within tissues during inflammation. Consistent with these findings direct administration of CRF and IL-1 to sites of localized inflammation or swim stress (which releases endogenous CRF), were shown to induce opioid receptor-specific analgesia. Furthermore, immune suppression by cyclosprine or irradiation resulted in a decrease in immune cell number and thereby decreased the analgesic action of CRF, IL-1 or swim stress in animals with inflammatory pain. In addition to these studies on the involvement of the immune system in peripheral analgesia we are also examining the activity of numerous peripherally selective opioid compounds in an effort to bypass the unwanted central side effects that plague opioids currently used in pain management.